5-amino-1-(chloromethyl)-1,2 dihydro-3H-benz [e]indoles: Relationships between structure and cytotoxicity for analogues bearing different DNA minor groove binding subunits
Gj. Atwell et al., 5-amino-1-(chloromethyl)-1,2 dihydro-3H-benz [e]indoles: Relationships between structure and cytotoxicity for analogues bearing different DNA minor groove binding subunits, J MED CHEM, 42(17), 1999, pp. 3400-3411
A series of 5-amino-seco-CBI compounds, designed for use as effecters for p
rodrugs, were prepared to study structure-activity relationships for the cy
totoxicity of side chain analogues. Compounds were prepared by coupling 1-(
chloromethyl)-5-nitro-1,2-dihydro-3H-benz[e]indole to appropriate carboxyli
c acids, followed by nitro group reduction, or by coupling suitable 5-amino
-protected indolines to alpha,beta-unsaturated acids, followed by deblockin
g. These AT-specific DNA alkylating agents were evaluated for cytotoxicity
in a series of tumor cell lines (AA8, UV4, EMT6, SKOV3). For those analogue
s bearing an indolecarbonyl side chain, the 5'-methoxy derivative was the m
ost cytotoxic (IC50 1.3 nM in AA8 cells, 4 h exposure), comparable to that
of the parent CBI-TMI (5',6',7'-trimethoxyindole) derivative (IC50 0.46 nM
in the above assay). A subset of solubilized derivatives bearing O(CH2)(2)N
Me2 substituents were about 10-fold less potent. For compounds containing a
n acryloyl linker in the side chain, the 4'-methoxycinnamoyl derivative pro
ved the most cytotoxic (IC50 0.09 nM in the above assay). A number of these
5-amino-seco-CBI-TMI analogues (including the solubilized compounds) are o
f interest both as cytotoxins and as components of amine-based prodrugs des
igned for tumor-specific activation.